U.S. patent application number 09/129402 was filed with the patent office on 2002-01-17 for dosage form comprising means for changing drug delivery shape.
Invention is credited to EDGREN, DAVID E., SKLUZACEK, ROBERT R..
Application Number | 20020006439 09/129402 |
Document ID | / |
Family ID | 22016109 |
Filed Date | 2002-01-17 |
United States Patent
Application |
20020006439 |
Kind Code |
A1 |
SKLUZACEK, ROBERT R. ; et
al. |
January 17, 2002 |
DOSAGE FORM COMPRISING MEANS FOR CHANGING DRUG DELIVERY SHAPE
Abstract
A dosage form is disclosed comprising means for delivering
essentially a total dose of drug.
Inventors: |
SKLUZACEK, ROBERT R.;
(NEWARK, CA) ; EDGREN, DAVID E.; (EL GRANADA,
CA) |
Correspondence
Address: |
PAUL B. SIMBOLI
ALZA CORPORATION
1900 CHARLESTON ROAD, M10-3
P. O. BOX 7210
MT. VIEW
CA
94039-7210
US
|
Family ID: |
22016109 |
Appl. No.: |
09/129402 |
Filed: |
August 5, 1998 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60058323 |
Sep 9, 1997 |
|
|
|
Current U.S.
Class: |
424/464 ;
424/465 |
Current CPC
Class: |
A61K 9/0004
20130101 |
Class at
Publication: |
424/464 ;
424/465 |
International
Class: |
A61K 009/20 |
Claims
We claim:
1. A dosage form for delivering a drug to a patient in need of the
drug, wherein the dosage form comprises: an orally administrable
therapeutic composition comprising a dose of drug and a
pharmaceutically acceptable polymer carrier for transporting the
drug from the dosage form; a membrane that surrounds the
therapeutic composition, which membrane comprises a polymer
permeable to the passage of fluid, a plasticizer, a surfactant, and
a binder; and an exit in the membrane for delivering the drug at a
sustained-release rate over an extended time.
2. The dosage form for delivering the drug according to claim 1,
wherein the membrane changes shape during the operation of the
dosage form.
3. A dosage form for delivering the drug according to claim 1,
wherein the binder is compatible with and binds the polymer,
plasticizer, and surfactant into the membrane.
4. The dosage form for delivering a drug to a patient in need of
the drug, wherein the dosage form comprises: an orally
administrable therapeutic composition comprising a dose of drug and
a pharmaceutically acceptable polymer carrier for transporting the
drug from the dosage form; a displacement composition comprising a
polymer that expands in the presence of an aqueous fluid and
thereby pushes the therapeutic composition from the dosage form; a
membrane that surrounds the therapeutic composition and the
displacement composition, which membrane comprises a polymer
permeable to the passage of an aqueous fluid, a plasticizer, a
surfactant, and a binder; and an exit in the membrane for
delivering the drug at a sustained-release rate over an extended
time.
5. The dosage form for delivering the drug according to claim 3,
wherein the membrane possesses a surface that faces the therapeutic
composition and the displacement composition and a surface that
faces the patient and carries thereon a dose of drug.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefits of provisional
application U.S. Ser. No. 60/058,323 filed Sep. 9, 1997 under 35
U.S.C. .sctn.119(e).
FIELD OF THE INVENTION
[0002] This invention pertains to both a novel and to a useful
dosage form. Particularly, the invention relates to a dosage form
capable of changing its shape. More particularly, the invention
concerns a dosage form comprising a drug and means that respond to
a physical-chemical influence, whereby the dosage form changes from
an initial to a total drug delivery shape.
BACKGROUND OF THE INVENTION
[0003] Dosage forms, and more particularly osmotic dosage forms
were disclosed by Theeuwes and Higuchi in U.S. Pat. Nos. 3,845,770
and 3,916,899. The dosage forms disclosed in these patents comprise
a wall that surround a therapeutic drug. The wall is permeable to
the passage of an external fluid, and it is substantially
impermeable to the passage of drug. The dosage forms comprise a
passageway through the wall for delivering the drug from the dosage
form. These dosage forms release the drug by fluid being imbibed
through the wall into the dosage form at a rate determined by the
permeability of the wall and the osmotic pressure gradient across
the wall. The dosage form thereby produces an aqueous solution
containing the drug that is dispensed through the passage way from
the dosage form. These dosage forms are effective extraordinarily
for delivering a drug that is soluble in fluid and exhibits an
osmotic pressure gradient across the wall against an external
fluid.
[0004] A pioneer advancement in dosage forms was presented to the
pharmaceutical-dispensing arts by inventor Theeuwes in U.S. Pat.
No. 4,111,202. In this patent, the delivery kinetics of the osmotic
dosage form is enhanced for delivering a drug that is insoluble to
very soluble in fluid, by manufacturing the dosage form with a drug
compartment and a displacement compartment separated by a piston.
The piston is movable from a first rested to a second rested state.
The osmotic dosage form delivers the drug by fluid imbibed through
the wall of the dosage form into the displacement compartment
thereby producing a solution that acts as a driving force that is
applied against the piston. This force urges the piston to move
against the drug compartment and correspondingly displace the drug
through a passageway from the dosage form. While this dosage form
operates successfully for its intended use, and while it can
deliver many drugs of varying solubilities, its use can be limited,
because of the complex manufacturing steps and the high cost needed
for fabricating and placing the piston in the dosage form.
[0005] In U.S. Pat. No. 4,327,725 patentees Cortese and Theeuwes
provided an osmotic dosage form for delivering a therapeutic agent
that because of its solubility in aqueous and biological fluids, is
difficult to deliver in therapeutic doses at a controlled rate over
time. The dosage form of this patent comprises a wall that is
semipermeable. The semipermeable wall surrounds a compartment
containing a therapeutic agent that is insoluble to very soluble in
aqueous and biological fluids and a separate osmogel. In operation,
the osmogel, a hydrogel, expands in the presence of external fluid
that enters the dosage form thereby causing the beneficial agent to
be dispensed through a passageway from the dosage form. This dosage
form operates successfully for its intended use, and it delivers
many difficult to deliver therapeutic agents for their intended
therapy.
[0006] Now, it has been observed unexpectedly, the above presented
dosage forms may not deliver their intended dose of therapeutic
agent, including a drug. This observation that these dosage forms
may not achieve their full delivery potential is attributed to
limitations in the prior art dosage forms. For instance, the dosage
forms may not deliver all of the needed dose, and the prior art
sought to compensate for this inherent limitation by manufacturing
the dosage form containing an over dose of drug. This over dose or
excess dose, often became trapped in the dosage form, or it led to
dose dumping of the drug. The dose dumping is accompanied by over
medication that may give rise to unwanted side effects. Then too,
an osmogel in the dosage form may be restricted from its maximum
expansion for displacing a drug from the dosage form due to the
rigidity or lack of flexibility of the membrane of the dosage
form.
[0007] It will be appreciated by those versed in the drug
dispensing art, that if a dosage from can be provided that delivers
all of its intended dose, substantially free of a over dose of
drug, such a dosage form would have a positive value and also
represent an advancement in the dispensing art. Likewise, it will
be appreciated by those versed in the dispensing art, that if a
novel dosage form is made available possessing physical properties
for delivering a prescribed need dose of drug substantially-free of
drug overage, the novel dosage form would find an immediate and
practical application in the fields of pharmacy and medicine.
OBJECTS OF THE INVENTION
[0008] Accordingly, in view of the above presentation, it is an
immediate object of this invention to provide a novel and
nonobvious dosage form that represents an improvement and an
advancement in the dispensing arts.
[0009] Another object of the invention is to provide an osmotic
system manufactured as a dosage form that overcomes the
disadvantages and limitations associated with the prior art dosage
forms.
[0010] Another object of the invention is to make available a
dosage form that delivers the required and needed dose of drug for
accepted therapy free of delivering an overage of drug.
[0011] Another object of the invention is to provide a dosage form
that keeps its physical integrity while delivering a therapeutic
dose of drug while avoiding and/or reducing the risks associated
with dose dumping of the drug.
[0012] Another object of the invention is to provide a dosage form
comprising means for changing from a rested state to a flexible
state and can deliver a dose of drug at a controlled-rate over a
sustained release period of time.
[0013] Another object of the invention is to provide a new and
useful dosage form that attains a zero-order release drug delivery
profile while administering a drug to a human patient.
[0014] Another object of the invention is to make available a
dosage form which dosage form during a drug delivery period is free
from fractures and thereby avoids delivering a full dose of drug
plus any drug overages in a shorter than the desired delivery
time.
[0015] Another object of the invention is to provide a dosage form
comprising a membrane that is flexible and thereby enable the
dosage form to change its shape and thereby deliver essentially its
total content of drug.
[0016] Another object of the invention is to provide a dosage form
comprising a membrane endowed with a high concentration of
plasticizer that enables the membrane to undergo change from a
fixed, rigid non-rounded shape to a flexible rounded shape and
thereby enhance the delivery of drug from the dosage form.
[0017] Another object of the invention is to provide a osmotic
delivery system manufactured as a dosage form that can administer a
complete pharmaceutical dosage regimen at a controlled rate and at
a sustained-release rate for a particular time period, the use of
which requires intervention only for the initiation and possible
termination of the regimen.
[0018] Other objects, features, aspects and advantages of the
invention will be more apparent to those skilled in the dispensing
art from the following detailed specification taken in conjunction
with the accompanying figures and accompanying claims.
BRIEF DESCRIPTION OF DRAWINGS
[0019] In the drawings, which are not drawn to scale, but are set
forth to illustrate various embodiments of the invention, the
drawing figures are as follows:
[0020] Drawing FIG. 1 is a view of a dosage form provided by the
invention for orally administering a therapeutic agent to the
gastrointestinal tract of a human.
[0021] Drawing FIG. 2 is an opened view of the dosage form of
drawing FIG. 1 for illustrating the structure of the dosage
form.
[0022] Drawing FIG. 3 is an opened view of the dosage form of
drawing FIG. 1 illustrating the structure of a different dosage
form provided by the invention for delivering a drug to an
environment of use comprising a fluid.
[0023] Drawing FIG. 4 is a view of a dosage form made available by
the invention wherein the dosage form comprises an inner subcoat
membrane and an outer overcoat membrane.
[0024] Drawing FIG. 5 is a view of a dosage form made available by
the invention comprising an outermost overcoat of instant release
therapeutic agent including a drug.
[0025] Drawing FIG. 6 depicts a dosage form made available by the
invention, which dosage form during its therapeutic agent operation
changed from a first original shape to a second expanded state.
[0026] Drawing FIG. 7 illustrates the drug release profile from
dosage forms over a twenty-four extended drug delivery period.
[0027] Drawing FIG. 8 illustrates the drug release profiles for
three different dosage forms manufactured by the invention.
[0028] In the drawings and in the specification like parts in
related figures are identified by like numbers. The terms appearing
earlier in the specification and in the description of the
drawings, as well as embodiments thereof, are further described
elsewhere in the disclosure.
DETAILED DESCRIPTION OF DRAWINGS
[0029] Turning now to the drawing figures, which drawing figures
are examples of the dosage forms provided by this invention, and
which examples are not to be construed as limiting the invention,
one example of the dosage form is illustrated in drawing FIG. 1 and
designated by the numeral 10. In drawing FIG. 1, dosage form 10
comprises a body member 11 comprising membrane 12 that surrounds
and encloses an internal compartment, not seen in drawing FIG. 1.
Membrane 12 of dosage form 10 comprises an exit 13 for connecting
the interior of dosage form 10 with the exterior environment of
dosage form 10. The dosage form 10 of drawing FIG. 1 illustrates a
controlled-release dosage form that delivers a therapeutic agent
including a drug over an extended time. The dosage form comprising
the controlled-release properties provided by this invention is
successful at maintaining therapeutic drug levels in blood or in
body tissue. The terms blood and body tissue refer to human
patients, zoo and farm animals. The dosage form provided by this
invention makes available to the practice of medicine
continuous-release, extended-release therapy. The phrase extended
release embraces sustained-release and prolonged-release over up to
a single day of therapy. The extended, prolonged and
sustained-release denotes a duration of drug delivery time over
that achieved by conventional drug delivery forms such as tablets
and capsules.
[0030] In drawing FIG. 2, dosage form 10, manufactured as an
osmotic dosage form, is seen in opened section. In drawing FIG. 2,
dosage form 10 comprises body 11, membrane 12, that surrounds and
defines an internal compartment 14. Membrane 12 comprises at least
one exit means 13 that connects compartment 14 with the exterior of
dosage form 10. Dosage form 10 can comprise more than one exit
means 13.
[0031] Membrane 12 of dosage form 10, comprises a composition that
is permeable to the passage of an exterior fluid present in a fluid
environment of use, including the fluid of the gastrointestinal
tract, and, membrane 12 is impermeable to the passage of a
therapeutic agent and other components in compartment 14. The
composition comprising membrane 12 is semipermeable, it is
nontoxic, inert, flexible, exhibits plasticity, the ability to
change shape in response to applied pressure, and is
pharmaceutically acceptable for delivering a therapeutic agent to
an environment of use including an animal and a human patient.
[0032] Membrane 12, in one manufacture comprises a membrane-forming
composition comprising a member selected from the group consisting
of a cellulose ester polymer, a cellulose ether polymer and a
cellulose ester-ether polymer. These cellulosic polymers have a
degree of substitution, DS on the anhydroglucose unit, from greater
than 0 up to 3 inclusive. By "degree of substitution" is meant the
average number of hydroxyl groups originally present on the
anhydroglucose unit comprising the cellulose polymer that are
replaced by a substituting group. Representative membrane 12
polymers comprise a member selected from the group consisting of
cellulose acylate, cellulose diacylate, cellulose triacylate,
cellulose acetate, cellulose diacetate, cellulose triacetate,
mono-, di- and tricellulose alkanylates, mono-, di- and
tricellulose alkenylates, mono-, di-, and tricellulose alkinylates
and mono-, di- and tricellulose aroylates. Exemplary polymers
include cellulose acetate having a DS of up to 1 and an acetyl
content of up to 31%; cellulose acetate having a DS of 1 to 2 and
any acetyl content of 21 to 35%; cellulose acetate having a DS of 2
to 3 and an acetyl content of 35 to 44.8%; and the like. More
specific cellulosic polymers comprise cellulose propionate having a
DS of 1.8, a propyl content of 39.2 to 45% and a hydroxyl content
of 2.8 to 5.4; cellulose acetate butyrate having a DS of 1.8, an
acetyl content of 13 to 15% and a butyryl content of 34 to 39%;
cellulose acetate butyrate having a acetyl content of 2 to 29%, a
butyryl content of 17% to 53% and a hydroxyl content of 0.5 to 4.7;
cellulose triacylates having a DS of 2.9 to 3, such as cellulose
trivalerate, cellulose trilaurate, cellulose tripalmitate,
cellulose trisuccinate and cellulose trioctanoate; celluloses
diacylate having a DS of 2.2 to 2.6, such as cellulose disuccinate,
cellulose dipalmitate, cellulose dioctanoate, cellulose
dipentanoate, co-esters of cellulose, such as cellulose acetate
butyrate, and cellulose acetate propionate.
[0033] Additional semipermeable polymers for providing membrane 12
comprise ethyl acrylate methylmethacrylate copolymers; acetaldehyde
dimethylcellulose acetate; cellulose acetate ethylcarbamate;
cellulose acetate methycarbamate; cellulose diacetate
propylcarbamate; cellulose acetate diethylaminoacetate;
semipermeable polyamide; semipermeable polyurethane; semipermeable
sulfonated polystyrene; semipermeable crosslinked selective polymer
formed by the coprecipitation of a polyanion and polycation, as
disclosed in U.S. Pat. Nos. 3,173,876; 3,276,586; 3,541,005;
3,541,006 and 3,546,876; semipermeable polymers as disclosed by
Loeb and Sourirajan in U.S. Pat. No. 3,133,132, semipermeable,
lightly crosslinked polystyrenes; semi-permeable crosslinked
poly(sodium styrene sulfonate); semipermeable crosslinked
poly(vinylbenzyltrimethyl ammonium chloride); and semi-permeable
polymers possessing a fluid permeability of 2.5.times.10.sup.-8 to
5.times.10.sup.-2 (cm.sup.2/hr.multidot.atm), expressed per
atmosphere of hydrostatic or osmotic pressure difference across the
semipermeable wall. The polymers are known to the polymer art in
U.S. Pat. Nos. 3,845,770, 3,916,899 and 4,160,020; and in Handbook
of Common Polymers, Scott, J. R. and W. J. Roff, 1971, CRC Press,
Cleveland Ohio. Membrane 12 comprises 35 wt % to 60 wt % of the
semipermeable, pharmaceutically acceptable polymer.
[0034] Membrane 12 comprises a plasticizer that make membrane
softer, flexible, distensible, and compatible with the ingredients
comprising membrane 12. Representative of plasticizers useful for
the plasticization of membrane 12, comprise adipic acid
plasticizers, azelaic acid plasticizers, benzoic acid plasticizers,
citric acid plasticizers, epoxy plasticizers, glycol plasticizers,
glycerols, phosphoric acid plasticizers, phthalic acid
plasticizers, ricinoleic acid plasticizers, sebacic acid
plasticizers, and trimellitic acid plasticizers. Examples of
specific plasticizers comprise a member selected from the group
consisting of monoacetin, diacetin, triacetin, glycerine,
polyethylene glycol, di-n-hexyl adipate, bio (2-ethylhexyl)
adipate, bio (2-ethylhexyl) azelate, diethylene glycol dibenzoate,
tri-n-butyl citrate, tri-n-butyl acetylcitrate, epoxidized soy oil,
diethylene glycol dipelargonate, triethylene glycol di
(2-ethylbutyrate), tri (2-ethylhexyl) phosphate, 2-ethylhexyl
diphenyl phosphate, dibutyl phthalate, dinonyl phthalate, diphenyl
phthalate, n-butyl acetyl ricinoleate, di-n-butyl sebacate, bio
(2-ethylhexyl) terphthelate, trio (2-ethylhexyl) trimellitate, and
trisisodecyl trimellitate. The concentration of a plasticizer in
membrane 12 is 15 wt % to 55 wt %. The plasticizers are known in
the art in Encyclopedia of Polymer Science and Engineering,
Supplement Volume, Acid-Base Interactions to Vinyl Chloride
Polymers, pp 568-573, (1989), published by John Wiley & Sons,
Inc.
[0035] Membrane 12 of dosage form 10 comprising the semipermeable
polymer and the plasticizer also comprises a pharmaceutically
acceptable surfactant. The surfactant for the purpose of this
invention is amphiphilic as it contains both a hydrophobic and a
hydrophilic group. Representative of surfactants that exhibit
solubility in aqueous and nonaqueous solvents are polyoxyethylene
fatty acid esters that includes polyoxyethylene monostearate,
polyoxyethylene sorbitan monopalmitate, polyoxypropylene glycols
that include polyoxypropylene glycol having a molecular weight of
950 and 3 moles to 85 moles of ethylene oxide, polyoxpropylene
glycol possessing a molecular weight of 1200 and 7 to 40 moles of
ethylene glycol, polyoxypropylene glycol possessing a molecular
weight of 1750 and 5 moles to 160 moles of ethylene oxide,
polyoxypropylene glycol having a molecular weight of 2050 and 10
moles to 110 moles of ethylene oxide, polyoxypropylene glycol
having a 2250 molecular weight and 5 moles to 200 moles of ethylene
oxide, polyoxypropylene glycol possessing a molecular weight of
2750 and 15 to 250 moles of ethylene oxide, and polyoxypropylene
glycol of 3250 molecular weight with 8 moles to 300 moles of
ethylene glycol. The amount of surfactant in membrane 12 is 0.5 wt
% to 40 wt %. The surfactants are known in Systematic Analysis of
Surface-Active Agents, by Rosen and Goldsmith, Vol. 12, pp 486-494,
(1972) published by Wiley-Interscience, Inc. The surfactants known
as Myrij.RTM. and Tween.RTM. are commercially available from the
JCI Americas, Inc., Wilmington, Del. The Pluronic.RTM. surfactants
are available from BASF Corp., Mt. Olive, N.J. Additional
surfactants that can be used for the purpose of this invention are
surfactants possessing a hydrophilic-lyophilic balance of 6 to 40
as represented by polyoxyethylene monostearate with a
hydrophilic-lipophilic balance (HLB) of 11.1, trolamine (HLB) of
12, and polyoxyethylene lauryl ether with (HLB) of 16.9. The
hydrophilic-lipophilic balance of surfactants are known in
Pharmaceutical Sciences by Remington, 17.sup.th Ed., Ch. 21, pp
324,(1985) published by Mark Publishing, Co.
[0036] Dosage form 10, when manufactured as an osmotic dosage form
with controlled-release properties comprises at least one exit 13
in the dosage form membrane 12. The phase controlled-release as
used herein, indicates that control is exercised over both the
duration and the profile of the drug-release pattern. The
expression passageway 13, as used for the purpose of this
invention, includes aperture, orifice, bore, pore, porous element
through which the drug can be pumped, diffuse, travel or migrate, a
hollow fiber, capillary tube, porous overlay, porous insert,
microporous member, and porous composition. The expression also
includes a compound that erodes or is leached from the membrane in
the fluid environment of use to produce at least one passageway in
dosage form. Representative compounds suitable for forming at least
one passageway, or a multiplicity of passageways, includes an
erodible poly(glycolic) acid or poly(lactic) acid member in the
membrane; a gelatinous filament; a water-removable poly(vinyl
alcohol); leachable compounds such as fluid removable pore-forming
polysaccharides, acid, salts, or oxides. A passageway or a
plurality of passageways can be formed by a leaching a compound
such as sorbitol, sucrose, lactose, fructose, or the like, from the
membrane to provide a controlled-release dimensioned
pore-passageway. The passageway can have any shape such as round,
triangular, square, elliptical, and the like, for assisting in the
controlled-metered release of drug from dosage form. Dosage form
can be constructed with one or more passageways in spaced-apart
relation on one or more surfaces of a dosage form. Passageway and
equipment for forming passageways are disclosed in U.S. Pat. Nos.
3,845,770 and 3,916,899 by Theeuwes and Higuchi; in U.S. Pat. No.
4,063,064 by Saunders et al.; and in U.S. Pat. No. 4,088,864 by
Theeuwes et al. Passageways comprising controlled releasing
dimension, sized, shaped and adapted as a releasing-pore formed by
aqueous leaching to provide a drug releasing-pore formed by aqueous
leaching to provide a releasing-pore of controlled release-rate are
disclosed in U.S. Pat. No. 4,200,098 by Ayer and Theeuwes; and in
U.S. Pat. No. 4,285,987 by Ayer and Theeuwes.
[0037] Dosage form 10 comprises in compartment 14 a therapeutic
agent 15, represented by dots. The phrase therapeutic agent 15 as
used herein includes medicines or drugs, nutrients, vitamins, food
supplements, and other beneficial agents that provide a therapeutic
or a health benefit to animals, including a warm-blooded animal,
humans, farm animals and zoo animals. The term drug includes any
physiologically or pharmacologically active substance that produces
a local or a systemic effect in a host. The drug that can be
delivered includes drug that act on the central nervous system,
depressants, hypnotics, sedatives, tranquilizers, muscle relaxants,
analgesics, anesthetics, hormones, contraceptives,
sympathomimetics, diuretics, antiparasites, hypoglycemics,
ophthalmics, and cardiovascular drugs. Representative of drug 15
comprises vancomycin, valoxifene, cyclosporin, lisinopril,
ondansetron, fluvoxamine, captopril, phentolamine, enalapril,
amisulpride, imipramine, carbamazepine, famciclovir, clomipramine,
penciclovir, pergolide, mesalazine, enitabas, talviraline,
clozapine, nevirapine, zidoviudine, ganciclovir alendronic,
imiquimod, naratriptan, sparflozacin, lamivudine, zidovudine,
omeprazole, aiclovir, valaceclovir, oxcarbazepine, ganciclovir,
amfebutamonc, cidofovir, doxazosin, ebastine, formoterol,
moexipril, penciclovir, sertraline, spirapril, fenfluramine,
dexfenfluramine, phentermine, fenphen, oxybutynin, felodipene,
metoprolol, saquinavir, ritonavir, indinavir, and nelfinavir. The
dose of drug in dosage form 10 is 0.5 mg to 650 mg.
[0038] Drug 15 can be in various forms, such as uncharged
molecules, molecular complexes, pharmaceutically acceptable salts
including hydrochloride, hydrobromide, sulfate, laurylate,
palmitate, phosphate, nitrate, nitrite, borate, acetate, maleate,
tartrate, oleate, and salicylate. For acid drugs, salts of metals,
amines, or organic cations, for example, quaternary ammonium can be
used for the operative drug. Derivatives of drugs, such as esters,
ethers, and amides can be used for administering a drug. A drug
that is water insoluble can be used in a form that is a water
soluble derivative thereof as a solute, and on its delivery is
converted by enzymes, or hydrolyzed by the body pH, or by other
metabolic processes to the original pharmaceutically active
form.
[0039] Compartment 14 contains a pharmaceutically acceptable
osmopolymer carrier 16 that aids in transporting drug 15 from the
dosage form. The osmopolymer 16, represented by dashes, is
homogeneously blended with drug 15. The osmopolymers comprise a
member selected from the group consisting of a polyalkylene oxide
possessing a 75,000 to 600,000 weight-average molecular weight, or
a carboxyalkylcellulose possessing a 25,000 to 150,000
weight-average molecular weight. Representative of polyalkylene
oxide comprises polyethylene oxide of 100,000 molecular weight,
polyethylene oxide of 200,000 molecular weight, polyethylene oxide
of 300,000 molecular weight, polypropylene oxide of 400,000
molecular weight, and polypropylene oxide of 600,000 molecular
weight. Representative of carboxyalkylcellulose comprise a member
selected from the group consisting of alkali carboxyalkylcellulose,
sodium or potassium carboxymethylcellulose of 40,000 molecular
weight, lithium, or sodium or potassium carboxymethyl-cellulose of
75,000 molecular weight, sodium carboxymethylcellulose of 90,000
molecular weight, and potassium carboxyethylcellulose of 125,000
molecular weight. The dosage form comprises 20 wt % to 100 wt % of
osmopolymer 16.
[0040] The therapeutic composition in dosage form 10 comprises a
hydroxypropylalkylcellulose 17 that imparts cohesive qualities to
the therapeutic composition comprising drug 15 and osmopolymer 16.
The binder imparts a cohesiveness to the composition during
manufacture and when an external fluid enters dosage form 10 the
binder improves the free-flowing qualities of the composition for
administration to a human patient. Representative of
hydroxypropylalkylcellulose possessing a 9,000 to 400,000
number-average molecular weight comprise a member selected from the
group consisting of hydroxypropylmethylcellulose,
hydroxypropylethylcellulose, hydroxypropylisopropylcellulose,
hydroxypropylbutylcellulose, and hydroxypropylpentyl-cellulose.
Representative of additional materials that can be used as binders
for the purpose of this invention comprise a member selected from
the group consisting of starch, gelatin, molasses and
polyvinylpyrrolidone. The amount of binder in the therapeutic
composition in drawing FIG. 2 is 0.5 wt % to 10 wt %.
[0041] The therapeutic composition comprises a lubricant 18 used
during the manufacture of the therapeutic composition to prevent or
reduce adhesion of the composition to the surfaces of dies and
punches. The lubricants comprise a member selected from the group
consisting of calcium stearate, zinc stearate, magnesium stearate,
magnesium oleate, calcium palmitate, sodium suberate, potassium
laureate, stearic acid, salts of fatty acids, salts of alicyclic
acid, salts of aromatic acids, oleic acid, palmitic acid and a
mixture of a salt of a fatty, alicyclic or aromatic acid. The
amount of lubricant in a therapeutic composition is 0.01 wt % to
3.0 wt %.
[0042] The therapeutic composition can comprise 0 wt % to 3 wt % of
a colorant 19. The colorant 19 makes the dosage form more esthetic
in appearance and it serves to identify the dosage form during
manufacture and in therapy. The colorants are represented by
FD&C Red No. 3; FD&C Red No. 40; FD&C Yellow No. 5;
FD&C Yellow No. 6; FD&C Blue No. 1; FD&C Blue No. 2;
FD&C Green No. 3; and iron oxide. The concentration of all
ingredients in a composition is equal to 100 wt %.
[0043] In drawing FIG. 3, dosage form 10 is seen in opened view for
illustrating the internal compartment 14. In drawing FIG. 3, dosage
form 10 comprises body member 11, membrane 12, exit 13 and internal
compartment 14. Internal compartment comprises the therapeutic
composition, which can be identified also as therapeutic layer 20
comprising drug 15, osmopolymer carrier 16, cohesive binder 17,
lubricant 18, and colorant 19, as described above in drawing FIG.
2. In drawing FIG. 3, dosage form 10 comprises a displacement
composition 21, also identified as expandable layer 21.
Displacement layer 21 comprises an expandable osmopolymer 22,
represent by V. The osmopolyer 22 comprises an osmopolymer having a
greater number molecular weight than the osmopolymer in the
therapeutic composition. The displacement layer 21 comprises a
member selected from the group consisting of polyalkylene oxide of
1,000,000 to 10,000,000 weight-average molecular weight.
Representative of polyalkylene oxides are polyethylene oxide of 1
million molecular weight, polyethylene oxide of 2 million molecular
weight, polypropylene oxide of 4 million molecular weight,
polyethylene oxide of 5 million molecular weight, and polyethylene
oxide of 7.5 million molecular weight. The osmopolymer 22 includes
carboxyalkyl-cellulose of 200,000 to 3,250,000 molecular
weight-average molecular weight. Representative of
carboxyalkylcellulose comprises a member selected from the group
consisting of lithium carboxymethylcellulose, potassium
carboxymethylcellulose of 200,000 molecular weight, sodium
carboxymethylcellulose of 200,000 molecular weight, sodium
carboxymethyl-cellulose of 1,250,000 molecular weight, potassium
carboxymethylcellulose of 1,500,000 molecular weight, sodium
carboxyethylcellulose of 2,250,000 molecular weight, and sodium
carboxymethylcellulose of 3,250,000 molecular weight. The
osmopolymer 22, also known as hydrogel or osmogel, exhibit the
ability to imbibe fluid and expand as a result of their osmotic
pressure gradient across membrane 12. The osmopolymer expands,
pushes, and displaces the therapeutic composition through exit 13
from dosage form 10. The amount of osmopolymer 22 in layer 21 is 40
wt % to 75 wt %.
[0044] Displacement, expandable layer 21 comprises 10 wt % to 40 wt
% of an osmagent 23, represented by a triangle. The osmagent 23 are
known as osmotically active compound and osmotically active solute.
The osmagent exhibits an osmotic pressure gradient across membrane
12, imbibes fluid into dosage form 10 that aids osmopolymer 21 to
expand and displace the therapeutic composition from dosage form
10. Representative of osmagent 23 comprise a member selected from
the group consisting of sodium chloride, potassium chloride,
magnesium sulfate, lithium chloride, lithium phosphate, sodium
phosphate, potassium sulfate, potassium sulfite, sodium sulfate,
sodium sulfate, potassium nitrate, and potassium phosphate.
[0045] Displacement layer 21 comprises a binder 24. Representative
of binder 24 comprise a member selected from the group consisting
of hydroxyalkylcellulose, hydroxypropyl celluloses,
hydroxypropylalkylcellul- oses and polyvinyls. The
hydroxypropylalkylcellulose possess a 9,000 to 400,000
number-average molecular weight comprising a member selected from
the group consisting of hydroxypropylmethylcellulose,
hydroxpropylethylcellulose, hydroxypropylbutylcellulose,
hydroxypropylpentylcellulose, and hydroxypropylhexylcellulose. The
polyvinyls of 1,200 to 360,000 viscosity-average molecular weight
comprising, a member selected from the group consisting of
polyvinylpyrrolidone, polyvinylcarbazole, polyvinylpyridine,
polyvinyloxazole, polyvinylmethyloxa-zolidone, polyvinylbutyrol,
polyvinylacetate, polyvinylalcohol, copolymer of
polyvinylprrolidone with vinyl acetate, copolymer of
polyvinylpyrrolidone and vinyl alcohol, copolymer of
polyvinylpyrrolidone with vinyl chloride, copolymer of
polyvinylpyrrolidone with vinyl fluoride, copolymer of
polyvinylpyrrolidone with vinyl butyrate, copolymer of
polyvinylpyrrolidone with vinyl laurate, and copolymer of
polyvinylpyrrolidone with vinyl stearate. The amount of binder in
the displacement composition is 0.5 wt % to 15 wt %.
[0046] Displacement layer 21 comprises 0 wt % to 2.75 wt % of a
colorant 25. The colorants are nontoxic and include Food and Drug
Administration colorants such as FD&C No. 1 blue, ferric oxide,
and the colorants disclosed above. Displacement layer 21 comprises
0.05 wt % to 3.75 wt % of a lubricant 26. The lubricant comprises a
member selected from the group consisting of sodium stearate,
potassium stearate, magnesium stearate, stearic acid, calcium
stearate, calcium palmitate, potassium oleate, and the lubricants
presented above. The concentration of the ingredients in layer 21
is 100 wt %.
[0047] Drawing FIG. 4 depicts another dosage form 10 made available
by the present invention. In drawing FIG. 4, dosage form 10 is seen
in opened view comprising the structure, ingredients, and
sustained-release rate programs presented accompanying drawing FIG.
2 and drawing FIG. 3. In drawing, FIG. 4, membrane 12 is defined as
an inner subcoat or subcoat 12. Subcoat 12 is in laminated,
contacting arrangement with overcoat 12 also identified as overcoat
membrane 27. Overcoat membrane 27 comprises 60 wt % to 99.5 wt % of
a hydroxypropylalkylcellulose possessing 9,000 to 400,000
number-average molecular weight. The hydroxypropylalkylcellulose
polymers for manufacturing membrane 27 comprise a member selected
from the group consisting of hydroxypropylmethylcellulose,
hydroxypropylethyl-cellulose, hydroxypropylbutylcellulose,
hydroxypropylpentylcellulose and hydroxypropylhexylcellulose.
Membrane 27 compresses 0.5 wt % to 30 wt % of a polyethylene
glycol. The polyethylene glycols possess a viscosity-average
molecular weight of 200 to 20,000. The polyethylene glycols are
neutral, hydrophilic polymers used to form membrane 27. The
polyethylene glycol used to provide membrane 27 for this invention
excludes polyethylene oxide. The polyethylene glycols are
commercially available from Union Carbide Corporation.
[0048] Dosage form 10 as seen in drawing FIG. 5 depicts another
manufacture provided by this invention. Dosage form 10 comprises a
therapeutic overcoat 28 on the outer surface, of dosage form 10.
The therapeutic overcoat comprises 0.5 mg to 50 mg of a drug and a
pharmaceutically acceptable carrier selected from the group
consisting of alkylcellulose, hydroxyalkylcellulose, and
hydroxypropylalkylcellulose. Representative of pharmaceutically
acceptable carriers include methyl-cellulose,
hydroxyethylcellulose, hydroxypropylmethylcellulose,
hydroxy-propylethylcellulose, and hydroxypropylbutylcellulose.
Therapeutic overcoat 28 comprising drug 29 provides therapy
immediately as therapeutic overcoat 28 dissolves, or undergoes
dissolution in the presence of gastrointestinal fluid present in a
human patient and concurrently therewith delivers drug 29 on
entrance into the gastrointestinal tract for immediate drug 29
therapy.
[0049] Dosage form 10 in drawing FIG. 6 is seen in operation
delivering the maximum dose of drug. In operation, as dosage form
10 enters a drug receiving environment, such as the
gastrointestinal tract of a patient, the dosage form changes in
shape from a first fixed state or shape 12a to a second different
state or shape 12b. As dosage form 10 moves in gastrointestinal
transit, plasticizer present in the membrane of the dosage form is
slowly dissolved and/or leached from the membrane. Simultaneously
therewith, fluid is imbibed into the dosage form generating
hydration pressure in the dosage form thereby causing membrane 12a
to change shape to membrane 12b. The dosage form becomes rounded
and/or spherical, thereby permitting the dosage form to push more
and/or all of its drug from the dosage form. As the dosage form's
previously angled edges near the exit are rounded, drug flows more
freely as afforded by the rounded membrane with less drug
maintained or trapped inside the dosage form. Thus, this in vivo
operation assures the delivery of a maximum dose of drug.
Process for Providing the Invention
[0050] The membrane of the dosage form can be formed by using the
air suspension procedure. This procedure consists in suspending and
tumbling the composition in a current of air and membrane-forming
composition until a membrane is applied to the drug forming
compartment. The air suspension procedure is well suited for
independently forming the membrane. The air suspension procedure is
described in U.S. Pat. No. 2,799,241; J. Am. Pharm. Assoc., Vol.
48, pp. 451-459 (1959); and ibid., Vol. 49, pp. 82-84 (1960). The
membrane can be formed with a membrane-forming composition in a
Wurster.RTM. air suspension coater using an organic solvent, such
as acetone-water cosolvent 90:10 (wt;wt) with 2.5 wt % to 7 wt %
polymer solids. An Aeromatic.RTM. air suspension coater using, for
example, a methylenedi-chloride methanol cosolvent comprising 87:13
(v.v) can be used for applying the membrane. Other membrane-forming
techniques, such as pan coating, can be used for providing the
dosage form. In the pan coating system membrane-forming
compositions are deposited by successive spraying of the
composition or the bilayered arrangement, accompanied by tumbling
in a rotating pan. A larger volume of cosolvent can be used to
reduce the concentration of polymer solids to produce a thinner
wall. Finally, the membrane of the coated compartments are laser or
mechanically drilled, and then dried in a forced air or humidity
over for 1 to 3 days or longer to free the solvent. Generally, the
walls formed by these techniques have a thickness of 2 to 20 mils
(0.051 to 0.510 mm) with a preferred thickness of 2 to 6 mils
(0.051 to 0.150 mm).
[0051] The dosage form of the invention in another embodiment is
manufactured by standard manufacturing techniques. For example, in
one manufacture the beneficial drug and other ingredients
comprising a therapeutic composition or forming the first layer
facing the exit means are blended, or the ingredients are blended
then pressed, into a solid layer. The drug and other ingredients
can be blended with a solvent and formed into a solid or semisolid
formed by conventional methods such as ball-milling, calendering,
stirring or roll-milling and then pressed into a selected shape.
The drug layer possesses dimensions that correspond to the internal
dimensions of the area the drug layer is to occupy in the dosage
from. Next, the drug layer is placed in contact with the
displacement layer. The layering of the drug layer and the
displacement layer can be fabricated by conventional press-layering
techniques. The bilayers possess dimensions corresponding to the
dimensions of the internal compartment or the dosage form. Finally,
the two-layer compartment forming members are surrounded and coated
with an outer membrane. A passageway is laser drilled or
mechanically drilled through the membrane to contact the drug
layer, with the dosage form optically-oriented automatically by the
laser equipment for forming the passageway on the preselected drug
surface.
[0052] In another manufacture, the dosage from is manufactured by
the wet granulation technique. In the wet granulation technique the
drug and the ingredients comprising the first layer are blended
using an organic or inorganic solvent, such as isopropyl
alcohol-methylene dichloride 80:20 (v.v) as the granulation fluid.
Other granulating fluid, such as water, isopropyl alcohol, or
denatured alcohol 100% can be used for this purpose. The
ingredients forming the first layer are individually passed through
a 40 mesh screen and then thoroughly blended in a mixer. Next,
other ingredients comprising the first layer are dissolved in a
portion of the granulation fluid, such as the cosolvent described
above. Then, the latter prepared wet blend is slowly added to the
drug blend with continual mixing in the in the blender. The
granulating fluid is added until a wet blend mass is produced,
which wet mass is then forced through a 20 mesh screen onto over
trays. The blend is dried for 18 to 24 hours at 25.degree. C. to
40.degree. C. The dry granules are then screened with a 16 mesh
screen. Next, a lubricant is passed through a 60 mesh screen and
added to the dry screened granule blend. The granulation is put
into milling jars and mixed on a jar mill for 2 to 10 minutes. The
first and second layered compositions are pressed into a layered
tablet, for example, in a Manesty.RTM. layer press.
[0053] Another manufacturing process that can be used for providing
the drug and displacement compositions comprise blending their
powdered ingredients in a fluid bed granulator. After the powdered
ingredients are dry blended in the granulator, a granulating fluid,
for example, poly(vinylpyrrolidone) in a solvent, such as in water,
is sprayed and mixed with the respective powders. The powders are
then dried in a granulator. This process is continued while
spraying the granulating fluid. After the granules are dried, a
lubricant, such as stearic acid or magnesium stearate, is blended
as above into the mixture. The granules are then pressed in the
manner described above. In another embodiment, when the fluid be
granulating process is used to manufacture the displacement layer,
an antioxidant present in the polyalkylene oxide can be removed
during the processing step. If antioxidant is desired, it can be
added to the displacement layer, this can be accomplished during
the fluid bed granulation described above.
[0054] The dosage form of this invention is manufactured in another
embodiment by mixing a drug with composition-forming ingredients
and pressing the composition into a solid layer possessing
dimensions that correspond to the internal dimensions of the
compartment space adjacent to a passageway. In another embodiment,
the drug and other drug composition forming ingredients and a
solvent are mixed into a solid, or semi-solid, by conventional
methods such as ball-milling, calendering, stirring, or
roll-milling, and then pressed into a preselected, layer-forming
shape.
[0055] In the manufactures as presented above, the manufacture
comprising a drug and an osmopolymer or osmagent are placed in
contact with the displacement layer, and the two layers are
surrounded with a semipermeable membrane. The layering of the drug
composition and the second displacement composition can be
accomplished by using a conventional two-layer tablet press
technique. The membrane can be applied by molding, spraying or
dipping the pressed shapes into wall-forming materials. Another
technique that can be used for applying the membrane is the
air-suspension coating procedure. This procedure consists in
suspending and tumbling the two layers in a current of air until
the membrane forming composition surrounds the layers.
Manufacturing procedures are described in Modern Plastics
Encyclopedia, Vol. 46, pp. 62-70 (1969); and in Pharmaceutical
Sciences, by Remington, 14t Ed., pp. 1626-1979 (1970) published by
Mack Publishing Co., Easton, Pa. The dosage form can be
manufactured by following the teaching the U.S. Pat. Nos.
4,327,725; 4,612,008; 4,783,337; 4,863,456; and 4,902,514.
[0056] Exemplary solvents suitable for manufacturing the membrane,
the composition layers and the dosage from include inert inorganic
and organic solvents that do not adversely harm the materials, the
wall, the layer, the composition and the drug. The solvents broadly
include members selected from the group consisting of aqueous
solvents, alcohols, ketones, esters, ethers, aliphatic
hydrocarbons, halogenated solvents, cycloaliphatics, aromatics,
heterocyclic solvents, and mixtures thereof. Typical solvents
include acetone, diacetone, alcohol, methanol, ethanol, isopropyl
alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl
n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone,
n-hexane, n-heptane, ethylene glycol monoethyl ether, ethylene
glycol monoethylacetate, methylene dichloride, ethylene dichloride,
proplylene dichloride, chloroform, nitroethane, nitropropane,
tetrachloroethane, ethyl ether, isopropyl ether, cyclohexane,
cyclo-octane, toluene, naphtha, 1,4-dioxane, tetrahydrofuran,
diglyme, aqueous and nonaqueous mixtures, such as acetone and
water, acetone and methanol, acetone and ethyl alcohol, methylene
dichloride and methanol, and ethylene dichloride and methanol.
DETAILED DISCLOSURE OF EXAMPLES
[0057] The following examples are merely illustrative of the
present invention and they should not be considered as limiting the
scope of the invention in any way, as these examples and other
equivalents thereof will become apparent to those versed in the art
in the light of the present disclosure and the accompanying
claims.
Example 1
[0058] An osmotic dosage form designed to deliver at controlled
rate the calcium-channel blocker, nifedipine, for once a day
treatment of angina and hypertension is fabricated according to
this invention. The dosage form consists of a layered tablet which
is coated with the specialized rate-controlling membrane that
changes shape as it functions. The layer of the tablet consists of
the active drug and other layer forming ingredients.
[0059] The drug layer of the dosage form is formulated by first
micronizing 200 grams of the drug to a particle size of
approximately 3-5 microns. Then, 745 grams of polyethylene oxide
having a molecular weight of approximately 200,000 grams per mole,
and 50 grams of hydroxpropylmethylcellulose having a hydroxypropyl
content of 10 weight percent, a methoxyl content of 29 weight
percent, and a molecular weight of 11,300 grams per mole, are
passed through a sieve having 40 wires per inch. All the components
are then dry mixed. To the mixture is added ethyl alcohol,
anhydrous, with stirring until a uniformly damp mass is produced.
The resulting mass is passed through a screen having 20 wires per
inch. The resulting granules are then air dried overnight at room
temperature. The dried granules are then passed through again a
screen having 20 wires per inch. Finally, 5 grams of magnesium
stearate, previously passed through a screen having 60 wires per
inch, is tumble mixed into the dried granules. The resulting
composition is compressed into tablets each weighing 150 mg.
[0060] The just prepared drug tablets are coated next with the
rate-controlling membrane of this invention. The membrane
formulation consisted of a subcoat and an overcoat. The subcoat
formulation was prepared by first dissolving 12 grams of
polyethylene glycol having a molecular weight of 400 grams per mole
in 1760 grams of water. Then, 14.4 grams of polyoxy-ethylene (20)
sorbitan tristearate was added with stirring while warming the
fluid to 40 degrees centigrade. When the 40 degree temperature was
reached, 105 grams of triacetin was added and the stirring rate was
increased. The heat was turned off and the fluid was allowed to
cool with stirring for one hour. Stirring was stopped and then the
fluid was allowed to cool at room temperature. After standing
overnight, the fluid was then stirred for 30 minutes. Then, 108
grams micronized cellulose acetate was slowly added to the vortex
of the fluid until fully dispersed in the fluid. The cellulose
acetate had a molecular weight of 40,000 grams per mole, an acetyl
content 39.8 weight percent, and had been air jet milled to a
nominal particle size of 5-10 microns. The resulting dispersion was
mixed for one hour.
[0061] Next, the membrane composition is charged into a fluidized
bed coater. Then, the batch of tablets is charged into the
fluidized bed coater. The membrane composition fluid while being
continuously stirred was applied by atomizing it through a standard
nozzle with air pressure of 0.8 barr at a spray rate of 9 grams per
minute. The bed of tablets was fluidized in a current of warm air
with an air flow of 140-160 cubic feet per minute, an inlet
temperature of 50-51 degrees centigrade, an outlet temperature of
33-34 degrees centigrade to reach a membrane thickness of 8 mils.
Next, the just membrane coated tablets were transferred to a forced
air oven thermostated at 50.degree. C. for 4 days. Then, a single,
round exit was drilled, (30 mils, 0.762 mm) through the membrane to
connect the drug composition with the exterior of the dosage form
for delivering at a sustained-release rate for its intended
therapy.
Example 2
[0062] The above procedure is repeated, except in this example the
drug is a member selected from the group consisting of doxazosin,
ebastine, fludarbine, formoterol, letrozle, lodoxamide moexipril,
penciclovir, sertaline, sparfloxacin, and spirapril.
Example 3
[0063] An osmotic dosage form designed to deliver at controlled
rate the calcium-channel blocker, nifedipine, for once a day
treatment of angina and hypertension is fabricated according to
this invention. The dosage form consists of a two layer tablet
which is coated with the invention's specialized rate-controlling
membrane which changes shape as it functions. One layer of the
tablet consists of the active drug and the other layer of the
tablet consists of a push layer.
[0064] The drug layer is formulated by first by micronizing 200
grams of the drug to a particle size of approximately 3-5 microns.
Then, 745 grams of polyethylene oxide having a molecular weight of
approximately 200,000 grams per mole, and 50 grams of
hydroxypropylmethylcellulose having a hydroxypropyl content of 10
weight percent, a methoxyl content of 29 weight percent, and a
molecular weight of 11,300 grams per mole, are passed through a
sieve having 40 wires per inch. All the components are then dry
mixed. To the mixture is added ethyl alcohol, anhydrous, with
stirring until a uniformly damp mass is produced. The resulting
mass is passed through a screen having 20 wires per inch. The
resulting granules are then air dried overnight at room
temperature. The dried granules are then passed through again a
screen having 20 wires per inch. Finally, 5 grams of magnesium
stearate, previously passed through a screen having 60 wires per
inch, is tumble mixed into the dried granules. The resulting
composition is referred to as the drug layer granulation.
[0065] A displacement or push layer granulation is formed by
passing 643 grams of polyethylene oxide having a molecular weight
of 5 million, 292 grams of sodium chloride, 50 grams of
hydroxpropylmethylcellulose having a hydroxypropyl content of 10
weight percent and a methoxyl content of 29 weight percent a
molecular weight of 11,300 grams per mole, and 10 grams of red
ferric oxide, through a screen having 40 wires per inch. These
components are dry mixed. Then, anhydrous ethyl alcohol is added to
the mixture with stirring to form a uniformly damp mass. The
resulting mass is passed through a screen having 20 wires per inch.
The resulting granules are air dried overnight at room temperature.
The dried granules are then passed through a screen having 20 wires
per inch. Finally, 5 grams of magnesium stearate, previously passed
through a screen having 60 wires per inch, is tumble mixed into the
dried granules. The resulting composition is referred to as the
displacement, or push layer granulation.
[0066] The two compositions, the drug composition and the
displacement composition were manufactured into two batches of
tablets fabricated by compressing these granulation composition
with {fraction (11/32)} inch diameter round standard concave
tooling on a press. One batch of tablets was made by filling 82.5
mg of push layer granulation into the die cavity and lightly
compacting the mass. Then, 165 mg of drug layer granulation was
placed over the lightly compacted push layer and laminated to it by
compressing both layers with a force of 1 ton. Each of the
resulting bilayer tablets of this batch contained 33 mg of
nifedipine which comprised a unit dose of 30 mg and an 10 percent
overage of 3 mg. Another batch of tablets were made without drug
overage. This batch was fabricated using the identical process
except that the weight of the drug layer in each tablet was
selected to be 150 mg. These tablets without overage contained a
unit dose of 30 mg without the 3 mg drug overage. It was observed
that the tablets of each batch had the sharp corners which are
commonly formed on tablets as a result of the compression step. The
sharp corners are commonly referred to in tablet technology as the
"land" of the tablet.
[0067] Next, both batches were then coated with the
rate-controlling membrane of this invention. The membrane
formulation consisted of a subcoat and an overcoat. The subcoat
formulation was prepared by first dissolving 12 grams of
polyethylene glycol having a molecular weight of 400 grams per mole
in 1760 grams of water. Then, 14.4 grams of polyoxyethylene (20)
sorbitan tristearate was added with stirring while warming the
fluid to 40 degrees centigrade. When the 40 degree temperature was
reached, 105.6 grams of triacetin was added and the stirring rate
was increased. The heat was turned off and the fluid was allowed to
cool with stirring for one hour. Stirring was stopped and then the
fluid was allowed to cool to room temperature. After standing
overnight, the fluid was then stirred for 30 minutes. Then, 108
grams micronized cellulose acetate was slowly added to the vortex
of the fluid until fully dispersed in the fluid. The cellulose
acetate had a molecular weight of 40,000 grams per mole, an acetyl
content 39.8 weight percent, and had been air jet milled to a
nominal particle size of 5-10 microns. The resulting dispersion was
mixed for one hour. This composition is referred to as the subcoat
coating fluid.
[0068] Then, in a separate mixing vessel, 1.4 grams of polyethylene
glycol in flake form and having a molecular weight of 8,000 grams
per mole was dissolved at room temperature with stirring into 186
grams of water. After the dissolution, 12.6 grams of
hydroxypropylmethyl cellulose having a hydroxypropoxyl content of
10 weight percent, a methyoxyl content of 29 weight percent, and a
molecular weight of 11,900 grams per mole was added with stirring
until dissolved. This composition is referred to as the overcoat
coating fluid.
[0069] Next, the two batches of tablets were simultaneously charged
into a fluidized bed coater. The subcoat coating fluid while being
continuously stirred was applied by atomizing it through a standard
nozzle with air pressure of 0.8 barr at a spray rate of 9 grams per
minute. The bed of tablets was fluidized in a current of warm air
with an air flow of 140-160 cubic feet per minute, an inlet
temperature of 50-51.degree. C., an outlet temperature of
33-34.degree. C. to reach a subcoating thickness of 8 mils. Then,
the overcoat coating fluid while being continuously stirred was
applied at a spray rate of 3 grams per minutes with an air flow of
130-155 cubic feet per minute, an inlet temperature of 41 degrees
centigrade, an outlet temperature of 33 degrees centigrade until an
overcoat thickness of 2 mils was accumulated. Each batch was then
transferred to a forced air oven thermostated at 50.degree. C. for
4 days. Then, a single, round exit was drilled with a 30 mil
diameter drill bit in the center of the drug layer side. This
completed fabrication of the dosage form. It was observed that the
land of the tablet had formed a template for the membrane coating
which coating also retained the shape of the underlying tablet
land.
[0070] Next, five samples of the dosage forms without drug overage
and five samples of the dosage forms with overage were then tested
in vitro. Each delivery system was agitated gently in 50 ml of
distilled water thermostated at 37.degree. C. for two hours. Then,
each system was transferred to a fresh 50 ml receptor and agitated
for another 2 hours. This process was repeated until twelve samples
of each dosage form had been collected, representing a delivery
performance covering a 24-hour period. It was observed that during
the initial few hours of the test, the sharp corner of the membrane
of each dosage form became rounded as the drug layer was pushed
against it internally by the swelling properties of the push layer.
rounded corners remained smooth and rounded for the entire duration
of the release test.
[0071] Upon completion of the release test, each of the above
receptor samples were then mixed with 35 ml of polyethylene glycol
having a molecular weight of 400 grams per mole. Also, the ten
membrane shells of the residuals of the systems were cut open with
a razor and the residual tablet material remaining within the
membrane shell was quantitatively transferred to a flask containing
50 parts water and 50 parts polyethylene glycol also having a
molecular weight of 400 grams per mole. The resulting mixture was
stirred until all of the soluble components within the residual
shell were flushed from the membrane shells and dissolved. The
release receptor solutions and solutions with residuals were then
photodegraded by shining a flood light on all the samples for 10
hours to produce a ultraviolet chromophore. The resulting samples
were then assayed by ultraviolet spectroscopy at a wavelength 282
nanometers. The release rate data and residual drug data were then
plotted and tabulated.
[0072] The in vitro performance results of the release test are
plotted in FIG. 7 and tabulated in Tables 1 and 2. In FIG. 7, the
cumulative release as a percent of 30 mg target dose is plotted as
a function of time where 100% represents 30 mg of drug released
over time. The drug of the study was nifedipine. The line with the
square symbols represent the average cumulative release of the
dosage form manufactured without a drug overage in the dosage form.
The line with cross symbols refer to the average cumulative release
of the dosage form comprising 10% overage of drug in the dosage
form. The release performance is identical through the time course
of the test up until the final 4 hours of release. At this point,
the performance of the two systems diverge. The system without
overage pumps 28.94 mg of the 30 mg target dose, representing more
than 96 percent of the target dose. By contrast, the system with
overage continues to deliver the drug overage which overage
delivery is actually more than it need deliver. The systems with
overage formulated in the core delivered 31.64 mg of the target 30
mg dose, representing more than 105 percent of the target dose.
[0073] Accompanying Table 1 presents the drug release performance
of a dosage form manufactured without overage of drug in the dosage
form. The drug in the study was nifedipine. The table plots the
cumulative amount in mg released per unit time over time, and the
minimum-average-maximum released over time. In the table SD denotes
the standard deviation and CV denotes the coefficient of variation.
The dosage form exhibited a 0.76 mg average residual and a 29.70 mg
average mass balance.
1 TABLE 1 CUMULATIVE AMOUNT RELEASED (MG) TIME 1 2 3 4 5 MINIMUM
AVERAGE MAXIMUM SD CV 2.00 .09 .11 .11 .12 .14 .09 .12 .14 .018
.154 4.00 2.28 3.15 3.11 3.54 2.87 2.28 2.99 3.54 .465 .156 6.00
5.42 7.07 6.91 7.57 6.60 5.42 6.71 7.57 .806 .120 8.00 8.60 10.71
10.33 11.50 10.41 8.60 10.31 11.50 1.062 .103 10.00 11.95 13.86
13.81 14.94 13.72 11.95 13.66 14.94 1.072 .079 12.00 14.76 16.89
17.18 18.29 16.90 14.76 16.81 18.29 1.278 .076 14.00 17.70 19.95
20.55 21.91 20.05 17.70 20.03 21.91 1.522 .076 16.00 20.55 23.38
24.07 25.39 23.35 20.55 23.35 25.39 1.768 .076 18.00 23.60 26.09
26.64 27.75 26.39 23.60 26.09 27.75 1.530 .059 20.00 26.13 27.98
28.48 28.67 28.58 26.13 27.97 28.67 1.063 .038 22.00 27.97 29.00
28.72 28.83 28.98 27.97 28.70 29.00 .424 .015 24.00 28.70 29.15
28.83 28.92 29.11 28.70 28.94 29.15 .190 .007
[0074] In accompanying Table 2, the release-rate performance for a
dosage form comprising an overage of drug nifedipine is set forth.
The dosage forms exhibited a 1.18 mg average residual and a 32.82
mg average mass balance.
2 TABLE 2 CUMULATIVE AMOUNT RELEASED (MG) TIME 1 2 3 4 5 MINIMUM
AVERAGE MAXIMUM SD CV 2.00 .11 .14 .12 .12 .14 .11 .13 .14 .013
.102 4.00 1.98 3.00 2.92 2.33 2.28 1.98 2.50 3.00 .439 .175 6.00
5.71 7.12 6.52 5.91 5.84 5.71 6.22 7.12 .590 .095 8.00 9.25 11.27
10.28 9.43 9.36 9.25 9.92 11.27 .858 .087 10.00 12.72 15.11 13.37
12.73 12.72 12.72 13.33 15.11 1.032 .077 12.00 16.00 18.63 16.39
16.23 15.93 15.93 16.64 18.63 1.131 .068 14.00 19.18 22.21 19.16
19.49 18.93 18.93 19.80 22.21 1.364 .069 16.00 22.32 25.77 22.52
22.86 21.94 21.94 23.08 25.77 1.537 .067 18.00 25.50 28.56 25.72
26.05 25.05 25.05 26.18 28.56 1.382 .053 20.00 27.94 30.71 28.12
28.56 27.73 27.73 28.61 30.71 1.213 .042 22.00 29.92 31.70 29.98
30.59 29.75 29.75 30.39 31.70 .799 .026 24.00 31.62 31.87 31.35
32.04 31.31 31.31 31.64 32.04 .318 .010
[0075] The performance of the dosage form can also be expressed in
terms of the amount of drug initially formulated within the dosage
form rather than based on the target 30 mg dose. The dosage form
without overage delivered 28.94 mg of the 29.7 mg of the assayed
quantity (the sum total of the cumulative drug release and the
residual drug not released) or more than 97 percent of the loading.
Similarly, the dosage form with overage delivered 31.64 of the
32.32 assayed quantity or more than 97 percent of the loading.
Thus, it is clear that dosage forms delivered more than 97 percent
of the loading whether an overage was initially present or not.
These data demonstrate that by using this specialized membrane, it
is not necessary to formulate a 10% overage initially in the dosage
form to achieve the target delivery dose.
Example 4
[0076] The procedure of Example 2 was followed in this example to
provide a dosage form comprising (1) a 300 mg drug composition
comprising 20.15 wt % nifedipine, 74.55 wt % polyethylene of
200,000 molecular weight, 5.04 wt % hydroxypropylmethylcellulose of
11,200 molecular weight, and 0.26 wt % magnesium stearate; (2) a
165 mg displacement composition comprising 64.50 wt % polyethylene
oxide of 7,500,000 molecular weight, 29.00 wt % sodium chloride,
5.00 wt % hydroxypropylmethylcellulose of 11,200 molecular weight,
1.00 wt % ferric oxide, and 0.50 wt % magnesium stearate; (3) a
109.6 mg inner membrane comprising 45.0 wt % cellulose acetate
consisting, 39.8% acetyl content, 41.0 wt % triacetin, 6.0 wt %
polyoxyethylene sorbitan monostearate, and 8.0 wt % polyethylene
glycol of 400 molecular weight; (4) a 9.3 mg outer membrane
comprising 90.0 wt % hydroxypropylmethylcellulose 606 of 11,900
molecular weight and 10.0 wt % polyethylene glycol possessing an
8,000 molecular weight; (5) a 30 mil (0.762 mm) exit; and, (6) a
13.6 hr release rate of 4.181 mg/hr. The dosage form comprised zero
percent drug overage. The procedure was followed to provide a
dosage form comprising a five percent drug overage and a ten
percent drug overage. Accompanying FIG. 8 plots the release profile
for a dosage form comprising 60 mg of nifidipine, wherein the line
with crosses denotes zero drug overage, the line with diamonds
denotes five percent drug overage, and the line with squares
denotes ten percent drug overage.
Example 5
[0077] The manufacturing procedures described herein are followed
to provide a dosage form according to the invention to comprise a
drug selected from the group consisting of tetrazosin
hydrochloride, felodipine, omeprazole, pergolide, clonidine
hydrochloride, pravastatin sodium, sumatriptan succinate,
acyclovir, diltiazem, oxybutynin, verapamil, lisinopril,
finasteride, simvastatin, doxazosin mesylate, and seleziline
hydrochloride.
Method of Practicing the Invention
[0078] The invention pertains additionally to the use of the
therapeutic dosage form by providing a method for delivering a drug
orally to a warm-blooded animal, including a human patient in need
of therapy. The method comprises admitting orally into a patient a
dosage form comprising a semipermeable membrane that surrounds a
therapeutic composition comprising a dose of drug that is
administered totally to a patient. The dosage form imbibes fluid
through the semipermeable membrane into the dosage form in response
to the concentration gradient across the semipermeable membrane.
The therapeutic composition in the dosage form generates osmotic
energy that causes the therapeutic composition to be administered
through an exit in the membrane over a prolonged period of time up
to 30 hours to provide controlled and sustained release
therapy.
[0079] In summary, it will be appreciated that the present
invention contributed to the art an unobvious dosage form that
possesses practical utility, can administer a drug at a
dose-metered release rate per unit time. While the invention has
been described and pointed out in detail with reference to
operative embodiments thereof, it will be understood by those
skilled in the art that various changes, modifications,
substitution and omissions can be made without departing from the
spirit of the invention. It is intended, therefore, that the
invention embrace those equivalents within the scope of the claims
which follow.
* * * * *